Characterization of the Role of Histamine in Children with Asthma

描述（由申请人提供）：哮喘是一种儿童发病率和死亡率很高的慢性疾病，是社会很大一部分人面临的重大健康问题。根据美国肺脏协会的数据，大约有2000万美国人患有哮喘，而且患病率还在继续上升。1980年至2003年间，儿童的发病率从3.6%上升到5.8%。尽管在过去几年中，哮喘的诊断和治疗取得了相当大的进展，但仍有相当一部分患者对吸入皮质类固醇等“核心”治疗没有反应。一些研究表明，吸入皮质类固醇治疗可能对多达三分之一的儿童无效，尽管专家建议将吸入皮质类固醇作为持续性哮喘儿童的首选治疗方法。我们现在了解到哮喘患者的潜在病理生理学是不同的；对某些患者群体有益的治疗方法可能对其他患者群体不起作用。抗组胺药过去曾被研究用于治疗哮喘。这些研究表明，抗组胺药可能对过敏性哮喘患者有益，组胺可能在疾病和治疗反应中发挥重要作用。然而，没有足够的证据将这些药物纳入哮喘的标准治疗。过去的研究没有集中在调查抗组胺药对明确哮喘表型的益处。此外，早期研究的抗组胺药的益处由于相关的副作用，如镇静，限制了它们的日常使用而受到阻碍。我们假设组胺在儿童过敏性哮喘的发病机制和治疗反应中起着明确的重要作用。我们计划通过两个具体目标来检验这一总体假设。第一个目的是描述组胺在过敏性哮喘和非过敏性哮喘中的相对作用。这一目标将通过比较过敏性哮喘儿童和非过敏性哮喘儿童的微血管对组胺的反应来实现，通过组胺离子导入和激光多普勒（HILD）监测来测量，以确定对组胺的药效学反应的潜在表型相关差异。我们还将研究遗传变异在两组间观察到的HILD差异中的作用。第二个目标将描述组胺反应过度的儿童与组胺反应较低的儿童通过HILD对抗组胺药的药效学反应。通过对左西替利嗪（LCT）在高组胺组和低组胺组中进行随机、双盲、安慰剂对照的交叉试验，观察两组抗组胺药效学的差异，实现这一目的。我们还将研究组胺途径的药代动力学变异和遗传变异对观察到的药效学药物反应的影响。我和我的导师一起设计了这个提案，将其作为一个密集的教育和研究经历，使我能够获得关键技能，成为一名独立的转化研究者，结合过敏/哮喘/免疫学和儿科临床药理学的知识和专业知识，开展研究，改善哮喘儿童的治疗结果。为此，儿童慈善医院和诊所为我的培训提供了一个理想的环境。我已经召集了一个核心小组，他们将在拟议的K23奖期间担任“指导团队”。这些非常有成就的人都拥有与我的研究和职业目标相关的互补专业知识，以及作为成功的、资金充足的独立研究者和导师的丰富经验。通过指导和合作，我将接受儿科临床药理学研究方面的特殊培训，重点是哮喘儿童的疾病特征和治疗反应。这份为期5年的职业发展奖金将为我提供：(1)来自有成就的研究人员的宝贵和必要的培训和指导，(2)支持时间获得针对我的研究和职业目标的有针对性的、相关的教学指导，(3)获得实际科学经验的时间，以及获得成功追求我的研究兴趣所需的特定专业知识和技术技能，以及(4)支持和保护必要的研究时间，以促进和确保我向独立研究者的过渡。再加上来自我所在机构的持续而重要的支持，NHLBI的K23资助将使我通过在奖励期间可能取得的成就为未来的成功奠定基础。

DESCRIPTION (provided by applicant): Asthma, a chronic disease which produces significant morbidity and mortality in children, is a significant health problem to a large segment of society. According to the American Lung Association, approximately 20 million Americans have asthma and prevalence rates continue to rise. In children, rates increased from 3.6% to 5.8% between 1980 to 2003. Despite considerable advances in the diagnosis and treatment of asthma over the past several years, a sizeable portion of patients do not respond to the "core" treatments such as inhaled corticosteroids. Some studies show that up to one-third of children may not respond to inhaled corticosteroid treatment although, inhaled corticosteroids are recommended by experts as the preferred treatment in children with persistent asthma. We are now learning that the underlying pathophysiology of disease is different among patients with asthma therefore; treatments which are beneficial in some patient groups may be not achieve affect in other groups. Antihistamines have been studied in the past for the treatment of asthma. These studies have shown that there may be a beneficial effect of antihistamines in patients with allergic asthma where histamine likely plays a large role in disease and treatment response. However, there is not enough evidence to include these drugs in the standard treatment of asthma. Past studies have not focused on investigating the benefit of antihistamines in well-defined asthma phenotype. In addition, the benefit of earlier investigated antihistamines was hindered due to associated side-effects such as sedation which limit their daily use. We hypothesize that histamine plays a definable, significant role in disease pathogenesis and treatment response in children with allergic asthma. We plan to test this overall hypothesis through two specific aims. The first aim will characterize the relative contribution of histamine in allergic vs. non-allergic asthma. This aim will be accomplished by comparison of the microvasculature response to histamine in children with allergic asthma and children with non-allergic asthma, measured by histamine iontophoresis with laser Doppler (HILD) monitoring, to determine potential phenotype-associated differences in the pharmacodynamic response to histamine. We will also investigate the role of genetic variation in the observed differences in HILD between the two groups. The second aim will characterize the pharmacodynamic response to antihistamines via HILD in children with an exaggerated histamine response compared to children with a low histamine response. This aim will be accomplished through conduct of a randomized, double-blind, placebo-controlled cross-over trial of levocetirizine (LCT) in the two groups (high histamine and low histamine) and observing the difference in antihistamine pharmacodynamics in the two groups. We will also investigate the effect of pharmacokinetic variation and genetic variation in the histamine pathway on the observed pharmacodynamic drug response. I, along with my mentors, have designed this proposal to be an intensive educational and research experience that will allow me to earn key skills to become an independent translational investigator combining knowledge and expertise in allergy/asthma/immunology and pediatric clinical pharmacology to conduct research which improves the therapeutic outcomes in children with asthma. To this end, Children's Mercy Hospitals and Clinics provide an ideal setting for my training. I have assembled a core group of individuals who will serve as the "mentoring team" for the duration of the proposed K23 award. Each of these highly accomplished individuals possesses complementary expertise pertaining to my research and career goal(s) and extensive experience as successful well-funded independent investigators and mentors. Through mentorship and collaboration I will receive exceptional training in pediatric clinical pharmacology research focused on characterization of disease and treatment response in children with asthma. Receipt of this 5-year career development award will provide me with: (1) valuable and necessary training and tutelage from accomplished researchers, (2) supported time to gain targeted, relevant didactic instruction specific to my research and career goals, (3) time for practical scientific experience along with acquisition of specific expertise and technical skills required to successfully pursue my research interests, and (4) support and protected research time necessary to facilitate and insure my transition to an independent investigator. Coupled with continued and significant support from my institution, a K23 grant from NHLBI would position me for future success through the achievements that will be possible during the period of the award. PUBLIC HEALTH RELEVANCE: These proposed investigations will fill critical gaps in knowledge concerning the role of histamine in asthma and treatment response in addition to establishing an innovative investigational paradigm for characterization of disease and therapeutic response.